Process for the production of delta5-androstene-19-ol and delta5-pregnene-19-ol compounds



t'tes te 3,955,228 Patented Nov. 29, 1962 Corporation, Panama, ama No Drawing. Filed May 14, 1962, Ser. No. 194,716 Claims priority, application Mexico Nov. 17, 1961 9 Claims; (Ci. 260-23955) The present invention relates to a novel process for the production of cyclopentano'phenanthrene derivatives.

More particularly the present invention relates to the process of transforming 5a-brorno-6t3,19-oxido androstane and pregnane derivatives into the corresponding A -androstene-19-ol and A -pregnene-19-ol compounds.

In US. Patents Nos. 2,001,989 and 3,008,957, in Ringold et al. U.S.P. appl. Serial No. 42,969, filed July 15, 1960, now Patent No. 3,036,068, and in Ringold et al. U.S.P. appl Ser. No. 45,790, filed July 28, 1960, now Patent No. 3,033,862, there has been disclosed a method for the production of 66,19-xido androstane and pregnane derivatives, consisting of treating a fl-hydroxy androstane or pregnane derivative with lead tetraacetate. When this process is applied to u-halo-6B-hydroxy steroids, the ex- 25 pected inhale-6,6, l9-oxido compounds are produced.

In accordance with the present invention the surprising discovery has been made, that when 5w"bIOlTlO6B,19- oxido compounds are treated with a reducing agent of the type hereinafter defined in detail, there are produced 30 the corresponding 19-hydroxy-A -derivatives in very high yields. Although other 50-h8.lO-6/3,19-OXld0 compounds, such as the 5ot-chloro-6fi,19-oxido derivatives, undergo this reaction, the same high yields cannot be attained.

assignor to Synteir 5 enema, a corporation of Pan The process of the present invention is represented by the following scheme:

I Q Y I CI-I R i \\4 R9 32 I Q I Q CH3 OH O i R 1 HO I III Q v j RO oHi I In the above formulas R represents a keto group, a

hydroxyl group or a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms: R represents hydroen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R represents an acyloxy group, a hydroxyl group, a keto group, an acetyl group or the dihydroxyacetone side chain protected by the l7,20;20,2tbismethylenedioxy grouping; Y represents or :0; Q may be a double bond or the group 1'13 R4 wherein R represents hydrogen, hydroxyl or a hydrocarbon carboxylic acyloxy group of less than. 12 carbon atoms and R represents hydrogen, a-methyl, B-methyl or a-hydroxyl; R and R together represent the group O\ /O Lower alkyl Lower allryl at the Cl6a, C47 position; when Q is a double bond, R is the acetyl group.

The acyl and acyloxy groups are derived from hydrocarbon carboXylic acids having less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or mixed aliphatic-cyclic chain, or aromatic, winch may be substituted with functional groups such as hydroxyl, alkoxy of up to 5 carbon atoms, acyloxy of up to 12 carbon atoms, nitro, amino or halogen. Typical such ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, arninoacetate and ,B-chloropropionate.

The starting compound (I) of the process outlined above is obtained in accordance with US. Pat. 3,001,989, U.S. Pat. 3,008,957, Ringold et a1. U.S.P. appl. Ser. No. 42,969, filed July 15, 1960, and Ringold et al. U.S.P. appl. Ser. No. 45,790, filed July 28, 1960, by condensation of the corresponding 3-acyloXy-5u-bromo-6B-ol derivative with lead tetraacetate to produce the corresponding 3- acyloxy-5m-bromo-6B,19-oxido compound. This derivative may be employed as the starting compound, as well as the corresponding free 3-alcohol resulting from the hydrolysis in slightly basic medium, or the 3 -ketone resulting from the oxidation of the latter compound. This starting compound (I) is selected from the group consisting of compounds of the androstane and pregnane series, having a hydroxyl group at C-3, preferably aceylated, or a keto group, having a bromine atoms at C506, and an oxygen bridge between C-65 and C-l9. At (r17 there may be preferably present a ketone, a 17fi-acyloxy group, a 17e-acetyl group with or Without a hydroXyl or acyloXy group at C-l7a, or the dihydroxyacetone side chain protected as the 17,20;20,2l-bismethylenedioxy derivatives. There may further be other groups in the molecule of the starting compound which do not interfere with the reactions, such as for example, when there is a 17fl-acetyl substituent, a double bond between 0-16 and (3-17, or a l6oz,17u-di0l, preferably protected as the acetonide; an ll-ketone, preferably in the case of compounds having a l7/3-dihydroxyacetone side chain; a methyl group at 1601 or 16,8, etc.

Examples of convenient starting compounds are: the diacetate of 5a-bromo-6/3,l9-oXido-androstane-3B,17/8- diol, the 3-acetate of 5u-br0mo-6fi,l9-oxido-pregnan-3fiol-20-one, the 3-acetate of 16a-methyl-5oc-bromo-6/3,l9- oXido-pregnan-3,B-ol-ZO-one, the S-acetate of lop-methyl- 5a-bromo-6fl,19-oxido-pregnan-3fi-ol-20-one, the 3-acetate of l6ot,l7a isopropylidenedioxy 50c bromo 6,8,19- oxido-pregnan-3,3ol--one, the 3,17-diacetate of 50abromo-Gfi,l9-oxido-pregnane-3B,17a-diol-20-one; the 3-acetate of 17,20;20,2l-bismethylene-dioxy-Soc-bromo-6fi,19- oxido-pregnan-3fi-ol-ll-one, 5a-bromo-6B,19-oxido-pregnane-3,20-dione, 17,20;20,2l-bismethylenedicxy-5oc-bromo-6;9,19-oxido-pregnane-3 ,1 l-dione.

When practicing the process object of the present invention, outlined above, the starting compound (I) is treated with a reagent selected from the group consisting of metals having an oxidation potential between +3045 and +0.126 volt, inclusive (measured at C.; see C. D. Hodgman, Handbook of Chemistry and Physics, Chemical Rubber Publishing Co., Cleveland, Ohio; 41st edition, year 1959- 1960, page 1733), salts which on ionization give cations having an oxidation potential between +0.61 and +0.25 volt, inclusive (loc. cit.), and metal iodides, preferably the iodides of alkali and alkali-earth metals, in an adequate solvent.

When carrying out the reaction with metals of oxidation potential higher than +1.5 volts, such as for example lithium, calcium, sodium, magnesium, etc., there are preferably employed solvents free from active hydrogen atoms, such as the aromatic solvents as benzene, toluene or xylene, ether such as ter-butyl ether or dioxane, halogenated hydrocarbons such as carbon tetrachloride, methylene chloride, etc.

When using metals with an oxidation potential lower than +1.5 volts, such as manganese or zinc for example, there are preferably used lower aliphatic alcohols, such as methanol, ethanol or isopropanol, or liquid hydrocarbon carboxylic acids of less than 12 carbon atoms such as acetic, propionic etc. If the reagent employed is a salt, either a cation of adequate oxidation potential or a metal iodide, the reaction is preferably conducted in a polar organic solvent inert to such salts, such as for example the lower aliphatic ketones, such as acetone, or the lower aliphatic alcohols. Examples of salts with a cation of oxidation potential between +0.61 and +0.25 volt are chromous chloride, vanadium (ous) chloride, etc.

Examples of the metal iodides used in the present reaction are sodium iodide, potassium iodide, calcium iodide, etc.

The reaction is also carried out with mixtures of a metal of oxidation potential between the limits set forth above and of a metal of oxidation potential in the lower limit, such as for example the zinc-copper couple,

When in the reaction there is used as solvent a hydrocarbon carboxylic acid, under the conditions set forth above, there are obtained the corresponding 19-acyloxy derivatives (II; R O; R=acyl) wherein the acyloxy group is derived from the acid used as solvent. With the other solvents there are obtained the corresponding free l9-alcohols (I-I; R O, R=H).

In the case of the 3-ketones (I; R=O), the substituents at C-l9 are determined by the rules mentioned above, but the position of the double-bond in the final products depends upon the solvent. If the reaction is conducted under strictly neutral conditions, the double bond stays in the position between C-5 and C6 (II; R O); on the other hand, traces of acids or bases cause the rearrangement of the double bond to the position between C4 and C5 (IV). This transformation may be easily effected after the reaction of opening of the oxygen bridge.

The compounds represented by Formula II (R acyloxy and/ or R=acyl) are conventionally saponified in basic medium to produce the corresponding free A -3fi,19-diols (III).

From the above it is evident that the new processes may be especially applied to the pregnane and androstane series.

The reaction conditions are not especially critical, for example, for treating a starting compound of the type set forth above, with zinc dust in ethanol the optimum reaction conditions are at the reflux temperature for an approximate time of 16 hours. However, the reaction may also be carried out at lower temperatures than at reflux, for a period of time which may be shorter or longer, which only causes variations in the yield of the final product.

The intermediates described above may be converted into the corresponding l9-nor derivatives by the methods illustrated by the following equation, wherein only rings A and B are represented:

IX VII VIII In the above formulas R has the same meaning set forth previously.

In accordance with the above equation, the A -3,l9- diols (111) may be oxidized, for example by the Oppenauer method, to give the corresponding A -19-al-3-ones (VI). The latter compounds may also be obtained by oxidizing the corresponding A -19-ol-3-ones (IV; R=H), for example by the Oppenauer method or with chromium trioxide in pyridine.

Both the A -19-al-3-ones (VI) as well as the A -19-0l-3- ones (IV; R=H) may be oxidized in almost quantitative yield to produce the corresponding A -3-one--19-oic acids (VII), for example with Jones reagent (8 N chromic acid in acetone solution).

The latter acids may also be prepared from the corresponding A -3,l9-diols by conventional bromination to the 5a,6fl-dibromo-3,19-diols, followed by oxidation for example with Jones reagent, to produce the 5oc,6/3-dibromo-3-one-19-oic acids which on debromination with an appropriate reagent, such as zinc in acetic acid, furnish the desired A -3-one-l9-oic acids.

The conversion of the A -3-ketones, with one or more oxygen atoms at C-19 (IV,VI, VII) into the corresponding 19-nor derivatives is carried out by known reactions:

For example, the production of the 19-nor-derivatives starting from l9-hydroxy or acyloxy-A -3-ketones by alkaline treatment of the latter, has been described by G. Winston Barber et al., J. Org. Chem., 20, 1253 (1955), A. S. Meyer, Experientia, 11, 99(1955), and A. Zaflaroni, British Patents Nos. 820,780 and 853,851; the preparation from A -19-al-3-ones by alkali treatment and from A -3- keto-l9-0ic acids by acid treatment, has been described by H. Hagiwara et al., Chem. Pharm. Bull. Japan, 8, 84 (1960).

In the latter reference there is also described a method for producing A -3-ketones (IX) from A -3-keto-l9- oic acids by heating with pyridine.

The application of these processes to the intermediate PREPARATION 1 To a solution of 5 g. of cortisone in 200 cc. of chloroform were added 40 cc. of 37% aqueous formaldehyde and 5 cc. of concentrated hydrochloric acid and the mixture was stirred for 48 hours at room temperature. The two layers were separated; the aqueous layer was washed with chloroform and the combined organic solution was washed with water to neutral, dried over anhydrous sodium sulfate and evaporated ot dryness. The residue was recrystallized from methanol-ether thus affording 17,20, 20,21-bismethylenedioxy-A -pregnene-3, 1 l-dione.

A solution of 5 g. of the above compound in 50 cc. of acetic anhydride and 5 cc. of acetyl chloride was boiled for 4 hours under an atmosphere of nitrogen. The reaction mixture then was distilled almost to dryness, cooled, diluted with ether and the organic extract washed with Water, then wtih 5% sodium bicarbonate solution and finally with water. There was thus obtained 3-acetoxy- 17,20;20,21-bismethylenedioxy-A -pregnadien-1l-one.

A solution of 5 g. of the preceding compound in a mixture of 100 cc. of 95% ethanol and 35 cc. of tetrahydrofuran was cooled to 10 C. and added dropwise, with occasional stirring over a 1 hour period, to a cold solution of 6 g. of sodium borohydride in 50 cc. of 30% ethanol, the reaction temperature not being allowed to exceed 5 C. After completion of addition, the solution was kept at -5 C. for 2 hours further; then 200 cc. of 10% sodium hydroxide was added and the solution boiled for 15 minutes. Most of the solvent was removed in vacuo, the residue acidified with 20% hydrochloric acid and the crystalline precipitate collected and washed.

Recrystallization of the crude material from acetone furnished 17,20:20,21-bismethylenedioxy-A -pregnen-3/3- ol-l l-one.

A mixture of 1 g. of the above compound 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with Water and dried. Crystallization from acetone-hexane gave the acetate of 17,20; 20,21-bismethylenedioxy-A -pregnen-3fi-ol-1 1-one.

PREPARATION 2 Reichsteins compound S was treated by the same techniques as described in the preceding preparation, producing consecutively: l7,20;20,2l-bismethylenedioxy-A pregnen-B-one, 3-acetoxy-17,20;20,2l-bismethylenedioxy- A -pregnadiene, 17,20;20,21-bismethylenedioxy-A -pregmen-3501, the acetate of 17,20;20,2l-bisrnethylenedioxy- A -pregnen-3,8-ol.

PREPARATION 3 There were suspended g. of diacetate of A -andro sten-3;8,17B-diol in 100 cc. of dioxane, 12 cc. of 0.46 N perchloric acid were added and then 4 g. of N-bromoacetamide; the N-bromoacetamide was added little by little, stirring over the period of 1 hour, in the absence of light and at a temperature of about 15 C. stirring was continued for 1 hour in darkness and at room temperature; the mixture was then decolorated by addition of a 10% aqueous sodium bisulfite solution there was added 1 liter of water and the mixture was extracted with methylene chloride; the extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated, under reduced pressure and at room temperature, thus giving 5a-bromo-androstane-3,B,6,3,17B-triol 3,17- diacetate.

3 Following the same technique, there were treated the compounds under I, thus affording the products under II.

3-aeetate of 17,20;20,2l-bismethylenedioxy 5a-brom0- pregnane-3B,6B-dioI-llone.

3-acetate of 17,20 20,21-bismethylenedioxy 5a-bromopregnane-Sflfifldiol.

PREPARATION 4 To a solution of 4 g. of the 3,17diacetate of Sa-bromoandrostane-3fi,6 3,l7B-triol in cc. of dry benzene, were added 6 g. of lead tetraacetate and the mixture was refluxed for 18 hours. It was cooled, filtered, water was added to the filtrate, the benzene layer was separated, washed with water and the benzene was evaporated under reduced pressure; upon chromatography of the residue on neutral alumina, there was obtained the diacetate of 5t .-bromo-6fi,19-oxido androstane-Bfi,17/3-diol.

The compounds under I were treated in the same manner, thus giving the products under H.

I II 3-acetate of 5abr0m0-preg 3acetate of 5e-brom0-6B,19

nane-3fiy6fi-diol-20-one. oxido-pregna11-.3[3o120-one.

3acetute of 17,20; 20,21-bismethylenedioxy 5u.bromo- 613,19 oxidopregnan-3B-0l ll-one.

3-acetate of 17,20; 20,21-bismethylenedioxy 5a-bromomethylenedioxy 5a-br0m0- pregnane-3/3,6B-d1ol. 65,19-oxid0pregnan'3/3-01.

PREPARATION 5 A suspension of 3 g. of the diacetate of 5ot-bromo- 6,8,19-oxido-androstane6fi,17fl-diol in cc. of methanol was treated with a solution of 3 g. of potassium carbonate in 18 cc. of water; the mixture was boiled under reflux for 1 hour and then cooled in ice and diluted with water. The formed precipitate was collected and by recrystallization from acetone-hexane yielded 5a-bromo-6;3,19-oxidoandrostane-3fl,17/3-diol. In the same manner, the rest of the compounds obtained in the foregoing preparation were transformed respectively into the following products: 5u-bromo-6fi,l9-oxido-pregnan-3B-ol-20-one, 5abromo-6fl,l9-oxido-A -pregnen-3B-ol-2O-one, 17,20;20,21- bismethylenedioxy 5e bromo-fip,19-oxido-pregnan 3,8- ol-ll-one, and 17,20;20,21-bismetl1ylenedioxy--5u-bromo- 6,8,19-oxido-pregnan-3p-ol.

PREPARATION 6 A solution of 2 g. of 5a-bromo-6fi,l9-oxido-androstane- 3/3,l7B-dio1 in 20 cc. of acetone was cooled to 0 C. and treated under an atmosphere of nitrogen and with stirring, with a solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture. It was stirred for 5 minutes further at 0-5 C. and diluted with water. The precipitate was collected, washed with water and dried under vacuum, thus affording a crude product which upon recrystallization from acetone-hexane gave 5ot-bromo6,8,l9-oxido-androstane-3,l7-dione.

The rest of the compounds obtained in the foregoing preparation were treated by the same method, giving respectively: 5a Monro-6,8,l9-oXido-pregnane3,ZO-dione, 5a-bromo-6p,19-oxido-A -pregnene-3,20-dione, 17,20,20, 21 bismethylenedioxy-Sa-bromo-6fi,19-oxido-pregnane-3, ll-dione and 17,20;20,21-bismethy1enedioxy-5a-bromo- 6,8,19-oxido-pregnane-3-one.

PREPARATION 7 The known compound, 3p,17u-diacetoxy-A -pregnen-20- Acetate of 17,20 20,21-bismethylenediown -pregnan- 3fl-01-11-one.

Acetate of 17,20 20,2l-bisniethylenedioxy A pregnenltfi-ol.

S-acetate of 17,20 20,2l-bismethylenedioxy 5a-br01nopregnaue-3flfiB-diol-11-one.

3-acetate 0t 17,20; 20,21-bis- 7 one, was successively treated according to Preparations 3 and 4 giving respectively: the 3,17-diacetate of Soc-bIOHlO- pregnane-3[3,6B,l7a-triol-20-one and the 3,17-diacetate of 5a-bromo-6fl,l9-oxido-pregnane-3fi,l7a-diol-20-one.

PREPARATION 8 The known compound, the acetate of l6ot-methyl-A pregnen-Zfl-ol-ZO-one, was treated according to Preparations 3 and 4, giving consecutively: the 3-acetate of 1604- rnethyI-Sa-bromo-pregnane-3(3,6{3-diol-20-one and the 3- acetate of 16a-methyl-Sa-bromo-6fi,l9-oxido-pregnan-3B- ol-20-one.

PREPARATION 9 The acetate of 16,8-methyl-A -pregnen-3fX-ol-ZO-one, obtained by conventional acetylation of the known compound, 16/3-methyl-A -pregnen-3,8-ol-20-one, in pyridine with acetic anhydride, was treated according to Preparations 3 and 4 giving successively: the 3-acetate of 165- methyl-5a-bromo-pregnane-3{3,6,8-diol-20-one and the 3- acetate of lfl-methyl-5a-bromo-6p,19-oxido-pregnan-3B- ol-20-one.

PREPARATION 10 The diacetate of 16ot-methyl-A -pregnene-3fi,17e-diol- -one, which is a known compound, was treated according to Preparations 3 and 4, giving successively: 3,17-diacetate of 16a-methyl-5m-bromo-pregnane-35,6,8,17ot-triol- 20-one and the 3,17-diacetate of 16a-methyl-5ot-bromo- 6 8,19-oxido-pregnane-3,B,l7oc-diol-20-one.

PREPARATION 11 16a,17a-isopropylidenedioxy A pregnen-3B-ol-20- one (G. Cooley et al., J. Chem. Soc., 4377 (1955)) was conventionally acetylated in pyridine with acetic anhydride, thus giving the corresponding 3-acetate, which was treated according to Preparations 3 and 4, giving successively: the 3-acetate of 16m,17a-isopropylidenedioxy-5abromo-pregnane-35,6,8-diol-20-one and the 3-acetate of 16a,l7a-isopropylidenedioxy 5a bromo 613,19 oxidopregnan-3 3-ol-20-one.

PREPARATION 12 The acetate of A -androsten-3fl-ol-17-one was treated according to Preparations 3 and 4, giving successively: the acetate of 5u-bromo-androstane-3B,6B-diol-17-one and the acetate of 5a-brorno-6B,19-oxido-androstan-3B-o1-17-one.

Example 1 A mixture of 5 g. of the diacetate of 5a-bromo-6p,19- oxido-androstane-3p,l7/3-diol, g. of zinc dust and 400 cc. of glacial acetic acid was refluxed under stirring for 16 hours, at the ends of which the mixture was filtered through celite. The filtrate was concentrated to a small volume under reduced pressure, cooled and diluted with ice water to precipitate the crude product. Recrystallization from acetone-hexane furnished the triacetate of A -androsten-3B,1718,19-triol.

Example 2 A mixture of l g. of the diacetate of 5u-bromo-6fi,19- oxido-androstane-3p,l7B-diol, 5 g. of zinc dust and 50 cc. of ethanol was refluxed for 16 hours and then filtered throught celite. The filtrate was evaporated to dryness and the residue crystallized from acetone-hexane, thus yielding the 3,17-diacetate of A -androstene-3fl,17fl,19- triol.

Example 3 A mixture of 5 g. of the diacetate of 5a-bromo-6p,19- oxido-androstane-3B,17p-diol, 10 g. of zinc dust and 350 cc. of glacial acetic acid was refluxed for 20 hours under vigorous stirring. The mixture was then worked up by the process described in Example 1, thus affording the triacetate of A -androstene-3p,175,19-triol.

Example 4 A mixture of l g. of the diacetate of 5a-bromo-6p,19- oxido-androstane-3B,l7/3-diol, 6 g. of zinc and 50 cc. of ethanol was refluxed for 12 hours, then filtered through celite and the filtrate was poured into water. The precipitate formed was collected by filtration, washed with water and dried. Recrystallization from acetone-hexane afforded the 3,17-diacetate of A -andr0stene-3B,175,l9- triol.

Example 5 Example 6 The diacetate of 5m-bromo-6fl,l9-oxido-androstane- 35,17l3-diol was treated by the method described in the preceding example, except that the sodium metal was substituted by lithium metal, thus affording a product identical with the one obtained in such example.

Example 7 The diacetate of 5a-bromo-6fl,l9-oxido-androstane- 3,8,17B-diol was treated in the same manner as in Example 5, except that calcium metal was used instead of sodium metal, thus affording a product identical with the one obtained in such example.

Example 8 The diacetate of 5a-bromo-6p,l9-oxido-androstane- 3/3,17fl-diol was treated by the method described in Example 5, except that the sodium metal was substituted by magnesium metal, thus giving a product identical with the one obtained in such example.

Example 9 The diacetate of Sa-bromo-QB,l9-oxido-androstane- 35,17fi-diol was treated in accordance with the method of Example 2, except that the zinc was substituted by manganese, thus obtaining a product identical with the one obtained in such example.

Example 10 The diacetate of 5or-bromo-6B,19-oxido-androstane- 3,8,l7fi-diol was treated in accordance with the method of Example 5, except that the benzene was substituted by xylene, thus giving the same product.

Example 11 The diacetate of 5e-bromo-6fi,19-oxido-androstane- 3,8,17,8-diol was treated in accordance with the method of Example 5, except that the benzene was substituted by terbutyl ether, thus giving the same product as in such example.

Example 12 The diacetate of Sa-brorno-6fl,19-oXido-androstane- 3,6,17,8-dio1 was treated in accordance with the method of Example 5, except that the benzene was substituted by carbon tetrachloride, thus afiording the same product.

Example 13 The starting compound of Example 1 was treated in c eeses accordance with the method described in that example, except that the acetic acid was substituted by propionic acid, thus giving the 3,17-diacetate-19-propionate of A androstane-3[3,l7,8,l9-triol.

Example 14 The starting compound of Example 2 was treated by the process described in that example, except that the ethanol was substituted by methanol, thus giving the same product.

Example The starting compound of Example 2 Was treated in accordance with the method of that example, except that instead of zinc dust there was employed zinc-copper dust. This reagent was prepared by suspending 5 g. of zinc dust in a solution of 3 g. of copper sulfate in 260 cc. of Water. The powder formed was used for the reaction, which yielded a product identical with the one obtained in the aforementioned example.

Example 1 6 To a solution of 1 g. of the diacetate of 5e-bromo 6p,19oxido-androstane-3fi,175-diol in 200 cc. of acetone was added at room temperature, under an atmosphere of nitrogen, 60 cc. of a recently prepared solution of chromous chloride (Rosenkranz et al., J. Am. Chem. Soc., 72, 4077 (1950)). After 5 minutes the acetone was removed under reduced pressure, water was added and the precipitate was collected and dried. Recrystallization from acetone-hexane afforded the 3,17-diacetate of A -androstene-3,B,l7;8,l9triol.

Example I 7 A mixture of 2 g. of the diacetate of Sa-bromo-QB, l9-oxido-androstane-3B,17;3-diol, 2 g. of sodium iodide and 50 cc. of methylethyl ketone was refluxed for 8 hours, then cooled, poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and evaporated to dryness. By crystallization of the residue from acetone-hexane there was obtained the 3,17-diacetate of d -androstene- 3,8,17/3,19-triol.

Example 19 The starting compound of the preceding example was treated by the method described in such example, except that the sodium iodide was substituted by potassium iodide, thus giving the same product.

Example 20 The starting compound of Example 18, was treated by the method described in that example, but calcium iodide was used instead of sodium iodide, thus giving the same product.

Example 2] The compounds under I were treated by the method described in Example 1, thus yielding the products under II.

3-acetate of 165 methyl-5abromo6fi,19-0xido-pregnan- 3 3-o1-20-one.

3-acetate of 1611.17 a isopropylidenedioxy 5a bromo-Gfi, 19-oxido pregnamB B-OI-ZO- one.

3,17-diacetate of 5a-bromo-6/3,

l9oxido pregnane-3fl,l7adiol-20-one.

3,1T-diacetate of 16arnethy1- 5a-bromo-GB,19 oxide-pregnone-35,17a-diol-20-one.

3-acetttte of fia-bromo 613,19- oxidoA -pregnen 3,5 01-20- one.

3-acetate of 17,20 20,21-bismethylenedioxy Smbromo- 6fl,19-oxtd0 pregnan 3fio1- ll-one.

3-ncetute of 17,20 20,21-bis methylenedioxy 5abromo- 6B,19-oxido-pregnan-3fi-o1.

3-acetate of 5a. bromo-6B,19-

oxido androstan 313-01-17- one.

3,19-diacetate or A -pregnene- 35,19-di0l-20-one.

3,19-diacetate of 16a-methyl- A pregnene 3B,19-dio120- one.

3,19-diacetate of 16B-rnethyl- A -pregnene 35,19 dio1-20- one.

3,19-diacetate of 16a,17a-is0- propylidenedioxy A pregnene-35,19-dio1-20-one.

Triacetate of M-pregnenefifl,

17a,19-trio1-20one.

Triacetate of methyl A pregnene 3B,17a,19-triol- O-one.

3,19-diacet'ate 0f A -pregnadiene-3fi,19-dio-1-20-one.

3,19-diacetate of 17,20 20,21- bismethyleuedioxy A -preg- 11ene-3fi,19-dio1-11-one.

3,19-diacetate of 17,20; 20,21- bismethylenedioxy A -pregnene-3fi,19dio1.

3,19-diacetate of A androsteue-3B,19-diol-17-one.

Example 22 The compounds under I, were treated by the process described in Example 2, thus affording the compounds under H.

3 acetate of methyl-5abrornc-6/3,19 oxide pregnan-3B-01-20-one.

3-acetate of 16a,17a-isopropylideuedioxy 5a bromo 65, 19-oxid0 pregnan-3B-o1-20- one.

3,17-diacetate of 5a-bromo-GB,

l9-oxido pregnane-3 8,17adio1-20-one.

3,17diacetate of Mia-methyl- 5a bromo 6B.19-oxidopregnane-3B,17a-diol-20-one.

3-acetate of 5a-bromo-6B,19-

oxido A pregnene 3fi-01- 20-one.

g acetate of 17,20 20,21-bismethylenedioxy 5a-brom0- 65,19 oxido-pregnan-3l3-ol- 11-one.

3-acetate of 17,20 20,21-bis methylenedioxy 5a-bromo- 6B,19-0xido-pregnan-3B-o1.

3-acetate of 5a Memo-613,19-

oxido androstan 3B-o1-17- one.

3-acetate of M-pregnene-bfl,

19-diol-20-one.

3-acetate of 16a methyl A pregnene-3fi,19-dio1-20-one.

S acetate of 16 3 methyl A pregnene-3 3,19--di01-20-one.

3-acetate of 1611,17 wisopropylideuedioxy A pregnene- 313,19-diol-20-one.

3,17-diacetate of Mpregnene- 3 3,17a,19-trio1 20-one.

3,17-diacetate of IGa-met-hyl- 5 pregnene 313,170.,19- trio1-20 one.

3-acetate of A -pregnadiene- 3B,19-diol-20-one.

3-acetate of 17,20 20,21-bismethylenedioxy A pregnene-3B,19-dio1 110ne.

3-acetate of 17,20 20,21-bismethylenedioxy A pregneue-3fl,19-dio1.

3-acetate of A -androstene-35,

19-di0I-17one.

Example 23 A solution of 2 g. of the 3,17-diacetate of A -androstene-3/9,17B,19-trio1 in 50 cc. of methanol was treated with 5 cc. of a 4% aqueous potassium hydroxide solution and the reaction mixture was stirred at 0 C. for 1 hour under atmosphere nitrogen; the mixture was then neutralized with acetic acid and the methanol was distilled under reduced pressure.

The residue was triturated with water and the solid was collected, Washed with water, dried and crystallized from ethyl acetate-methanol, thus yielding A -androstene- 3fi,17fi,19-triol. t

By the same process there were treated the compounds under I to produce the corresponding compounds under H.

3-acetate of A -pregnene-3B,19-

dio1-20-one.

3-acetate of 16a methy1-A pregnene-3B,19-dio1-20-one.

3-acetate of 165 methyl A pregnene-3B,19-diol-20-one.

3-acetate of 16a,17a-isopropy1- ideuedioxy A pregnene- 35,19-dio1-20-one.

3,17diacetate of A -pregnene- 3B,17a,19-triol-20-one.

3,17-diacetate of 16a.methy1- A pregnene 313,170.,19- -triol-20-0ne.

3-acetate of A -pregnadiene- 35,19-dio1-20-oue.

3-ace ate of 17,20; 20,21-bismethylenedioxy A pregnene3B,l9-diol-11-0ne.

3-ace ate of 17,20 20,2'1-bismethylenedioxy A preg- Ilene-318,19-dio1.

ii-acetate of A -androstene-3B,

19-dlo1-17-one.

II A -pregnene-35,19-di01-20-0ne.

16a methyl A pregnene- 35,19-dio1-20-0ne.

165-methyl A pregnene-35,

19-diol-20-one.

16a,17a isopropylidenedioxy- A pregnene-3B,19diol-20- one.

17-aeetate of A -pregnene-3B,

17 a,19-trio1-20-one.

l7-acetate of 16a-methyl-A pregnene 3/3,l7a,19-triol snn 17,20 20,21 bismethylenedh oxy A pregnene-3fl,19- diol-ll-one.

17,20 20,21 bismethylenedioxy-A -preg'nene-tifi,19-dio1.

pregnadiene-3B,19-diolne.

A -androstene 313,19-di01-17- one.

Example 24 A mixture of 1 g. of the 3,

19-diacetate of 17,20;20,21-

pregnene-BB,17a,l9,21-tetrol-11,20-dione.

Example 25 The compounds under I, were treated by following the process described in Example 1, except that the reflux time was of 3 hours, thus afiording the corresponding products under II.

5a-bromo 65,19 oxido androstan-3l3,17B-dio1.

5a-bromo 613,19 oxide-A pregnene-3B-01-20-one.

17,20 20,21 bismethylenedioxy 5a-bromo-6B,19-0xidopregnan-3Bo111-one.

17,20 20,21 bismethylenedioxy-Sa-bromo 65,19-xid0- pregnan-3B-ol.

19-acetate of A androstene- 3fi,17fl,19-triol.

19-aeetate of A pregnene-3B,

l9-diol-20-one.

19-acetate of A preguadiene-3B,19dio1-20-one.

19 -acetate of 17,20 2021- bismethylenedioxy A -pregneue3B,l9-dio1-11-one.

19-acetate of 17,20 2021- bismethylenedioxy A -pregnene-3fl,19-diol-11-one.

Example 26 The starting compounds of the preceding example were treated in accordance with Example 2, thus giving respectively the following compounds: A -androstene-3B, 17B, 19-triol, A -pregnene-3B,19-diol20-one, A -pregnadiene- 318,19 diol 20 one, 17,20;20,21-bismethylenedioxy-A pregnene-3B,19-diol-1l-one, and 17,20;20,21-bismethyl enedioxy-A -pregnene-3fl,19-diol.

12 xample 27 The starting compounds under I, were treated by the method of Example 1, thus furnishing the corresponding products under H.

5a-br0mo 6,3,19-0xido-androstane-3,17dione.

5a-bromo 618,19 oxide-pregname-3,20-dione.

fia-bromo 66,19 oxide A pregnene-3,20-dione.

17,20 20,21 bismethylenedioxy-5a-bromo 613,19-oxid0- pregnane-3,11-dione.

19-acetate of A androsten- 19-o1-3,l7-dione.

19-aeetate of A pregnene-19- o1320-dione.

19-acetate of A -pregnadien- 19-ol-3,20-dione.

19-acetate of 17,20; 20,21-bismethylenedioxy A pregnene19-o1-3,11-dione.

19-acetate of 17,20; 20,21-bismethylenedioxy A pregnen-19-ol-3-one.

Example 28 The starting compounds of the preceding example were treated in accordance with the method of Example 2, thus giving respectively: A -androsten19-ol-3,20-dione, A pregnadiene,19-ol-3,20-dione, 17,20;20,21 bismethylenedioxy-A -pregnen-19-ol-3,1l-dione, and 17,20;20,21-bismethylenedioxy-M-pregnen-19-ol-3-one.

I claim:

1. A process for the production of a compound selected from the group consisting of 19-hydroxy-A -androstene and 19-hydroxy-A -pregnene derivatives, which comprises treating the corresponding compound selected from the group consisting of 5a-bromo-6,6,l9-oxido androstene and 5ot-bromo-6,8,19-oxido pregnane derivatives with a reagent selected from the group consisting of metals with an oxidation potential between +3045 and +1.51 volts inclusive, in solvents free from active hydrogen atoms, metals with an oxidation potential between +1.5 and +0.126 volts inclusive, in lower aliphatic alcohols, metals with an oxidation potential between +1.5 and +01% volts inclusive, in liquid hydrocarbon carboxylic acids of less than 12 carbon atoms, salts which on ionization give cations with an oxidation potential between +0.61 and +0.25 volt inclusive, in lower aliphatic ketones, salts which on ionization give cations with an oxidation potential between +0.61 and +0.25 volt inclusive in lower aliphatic alcohols, metal iodides in lower aliphatic ketones, and metal iodides in lower aliphatic alcohols.

2. The process of claim 1, wherein the reagent is zinc in a lower aliphatic alcohol.

3. The process of claim 1, wherein the reagent is zinc in a liquid hydrocarbon carboxylic acid of less than 12 carbon atoms.

4. The process of claim 2, wherein the alcohol is ethanol.

5. The process of claim 3, wherein the acid is acetic acid.

6. The process of claim 1, wherein the reagent is Zinccopper couple in a lower aliphatic alcohol.

7. The process of claim 1, where the reagent is sodium metal in a solvent free from active hydrogen atoms.

8. The process of claim 1, wherein the reagent is chromous chloride in a lower aliphatic ketone.

9. The process of claim 1, wherein the reagent is sodium iodide in a lower aliphatic ketone.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,065,228 November 20 1962 Albert Bowers It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 12 line 30, for "androstene" read androstane Signed and sealed this 26th day of May 1964.

(SEAL) Attest:

EDWARD J. BRENNER Attesting Officer UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,065,228 November 20 1962 Albert Bowers he above numbered petthat error appears in t Patent should read as It is hereby certified (1 that the said Letters ent requiring correction an corrected below.

Column 12, line 30 for "androstene" read androstane Signed and sealed this 26th day of May 1964.

ERNEST W. SWIDER Attesting Officer Commissioner of Patents Notice of Adverse Decision in Interference In Interference No. 93,402 involving Patent No. 3,065,228, A. Bowers, PROCESS FOR THE PRODUCTION OF A -ANDROSTENE-19-OL AND M-PREGNENE-lS-OL COMPOUNDS, final judgment adverse to the patentee was rendered Aug. 30, 1965, as to claims 1, 3 and 5.

[Ofiicz'al Gazette December 14, 1965.] 

1. A PROCESS FOR THE PRODUCTION OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 19-HYDROXY-$5-ANDROSTENE AND 19-HYDROXY-$5-PREGNENE DERIVATIVES, WHICH COMPRISES TREATING THE CORRESPONDING COMPOUND SELECTED FROM THE GROUP CONSISTING OF 5A-BROMO-6B,19-OXIDO ANDROSTENE AND 5A-BROMO-6B,19-OXIDO PREGNANE DERIVATIVES WITH A REAGENT SELECTED FROM THE GROUP CONSISTING OF METALS WITH AN OXIDATION POTENTIAL BETWEEN +3.045 AND +1.51 VOLTS INCLUSIVE, IN SOLVENTS FREE FROM ACTIVE HDYROGEN ATOMS, METALS WITH AN OXIDATION POTENTIAL BETWEEN +1.5 AND +0.126 VOLTS INCLUSIVE, IN LOWER ALIPHATIC ALCOHOLS, METALS WITH AN OXIDATION POTENTIAL BETWEEN +1.5 AND + 0.126 VOLTS INCLUSIVE, IN LIQUID HYDROCRABON CARBOXYLIC ACIDS OF LESS THAN 12 CARBON ATOMS, SALTS WHICH ON IONIZATION GIVE CATIONS WITH AN OXIDATION POTENTIAL BETWEEN +0.61 AND +0.25 VOLT INCLUSIVE, IN LOWER ALIPHATIC KETONES, SALTS WHICH ON IONIZTION GIVE CATIONS WITH AN OXIDATION POTENTIAL BETWEEN +0.61 AND +0.25 VOLT INCLUSIVE IN LOWER ALIPHATIC ALCOHOLS, METAL IODIDES IN LOWER ALIPHATIC KETONES, AND METAL IODIDES IN LOWER ALIPHATIC ALCOHOLS. 